title: Non-additive interactions between mitochondrial complex IV blockers and hypoxia in rat carotid body responses.
abstract: The metabolic hypothesis of carotid body chemoreceptor hypoxia transduction proposes an impairment of ATP production as the signal for activation. We hypothesized that mitochondrial complex IV blockers and hypoxia would act synergistically in exciting afferent nerve activity. Following a pre-treatment with low dosage sodium cyanide (10-20μM), the hypoxia-induced nerve response was significantly reduced along with hypoxia-induced catecholamine release. However, in isolated glomus cells, the intracellular calcium response was enhanced as initially predicted. This suggests a cyanide-mediated impairment in the step between the glomus cell intracellular calcium rise and neurotransmitter release from secretory vesicles. Administration of a PKC blocker largely reversed the inhibitory actions of cyanide on the neural response. We conclude that the expected synergism between cyanide and hypoxia occurs at the level of glomus cell intracellular calcium but not at downstream steps due to a PKC-dependent inhibition of secretion. This suggests that at least one regulatory step beyond the glomus cell calcium response may modulate the magnitude of chemoreceptor responsiveness.
authors.affiliation: Department of Pediatrics, Division of Respiratory Medicine, Yale University School of Medicine, New Haven, CT 06520, USA. Electronic address: David.Donnelly@Yale.edu.
authors.forename: David F
authors.initials: DF
authors.lastname: Donnelly
authors.forename: Insook
authors.initials: I
authors.lastname: Kim
authors.forename: Eileen M
authors.initials: EM
authors.lastname: Mulligan
authors.forename: John L
authors.initials: JL
authors.lastname: Carroll
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000255:Adenosine Triphosphate / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D002118:Calcium / Q000378:metabolism; D002344:Carotid Body / Q000166:cytology* / Q000378:metabolism* / Q000503:physiopathology*; D002395:Catecholamines / Q000378:metabolism; D002628:Chemoreceptor Cells / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D003576:Electron Transport Complex IV / Q000037:antagonists & inhibitors / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D000860:Hypoxia / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D051381:Rats; D012966:Sodium Cyanide / Q000494:pharmacology
chemical_list: D002395:Catecholamines; D004791:Enzyme Inhibitors; D000255:Adenosine Triphosphate; D003576:Electron Transport Complex IV; D012966:Sodium Cyanide; D002118:Calcium
keywords: Calcium; Carotid body; Chemoreceptors; Hypoxia; Mitochondria